In the pharmaceutical industry, the accuracy of the metered doses of medicinal mixtures is of importance. These mixtures often contain active drug components that are harmful if the given dose is too high. On the other hand, the desired effect of the medicament is not achieved if the dose is too low.
The majority of pharmaceutical bulk products like powders, granulations and pellets are dosed volumetrically, due to process speed and cost effectiveness. By individually metering a volume of each dose before the dose is packaged, an accurate way of ensuring correct dosing is achieved.
Volumetric dosing can be performed by gravimetric feeding of the components to be dosed, or by forced feeding where, for example, one or more scrapers, rotating augers or rotating means making use of centrifugal force are used to feed medicament into a dosing chamber with a predetermined volume. To generate the correct dose, the volumetric dosing chamber is provided with slides opening and closing the dosing chamber during a cycle, for feeding and emptying the dosing chamber, respectively.
In some fields of pharmaceutical manufacturing 100% check-weighing is a common technology, where a filled package is check-weighed and the mean weight of the empty package (tare weight) is subtracted to calculate the fill-weight (“tare-gross-weighing”). This method providing an indirect weighing of the dose of medicament is often used when filling medicament in e.g. capsules. The capsules are weighed empty, then filled with medicament and then weighed again together with the contents. By subtracting the result of the first measurement from the second, an indirect indication of the weight of the medicament will be obtained.
This method of indirect weighing is also applicable for other packages, such as sachets. Thus, the sachet is weighed empty, then filled with the medicament, and then weighed again together with the contents, and the two measurements are subtracted for indirectly obtaining the weight of the medicament.
When the variance of the tare weight is equal to or greater than the target fill weight, the tare weights of the single receptacles have to be determined individually to calculate single fill weights. Further, when the tare weight of the receptacle is a multiple of the fill weight of the dose, the tare-gross-weighing approach is not applicable any more. For those cases, due to the relatively high preload of the receptacles, weighing cells with sensitivity and resolution appropriate for the dose to be weighed cannot be used. Further, this indirect weighing approach is not accurate enough when the weight of an active ingredient is considerably smaller than the weight of the package. The amount of active ingredient in a single dose might weigh as little as 1 mg, while the excipient with which they are to be mixed may weigh much more, in some cases up to a thousand times more, one or more grams.
However, the method of indirect weighing is not sufficient enough if high accuracy is needed since individual packages may vary in weight due to variations in, for example moisture content, surface weight and size.
Usually, medicaments contain one or more active ingredients to be mixed with in-active ingredients. In some cases, mixing of the components prior to filling the mixture in separate doses are not an alternative due to problem with segregation of the mixture during handling. This might be the case for example when mixing components with different properties, such as flow properties, density and/or particle-size. The result of mixing larger volumes before filling in separate doses might in those cases be an unreliable amount of active content in each dose. For those cases, there are methods of volumetrically dosing each and every component separately.
Volumetric dosing is in spite of the issues mentioned above widely used. By using well investigated formulations, balancing different needs it is possible to manage the issues mentioned. For pediatric formulations the issues with accuracy and precision is even more pronounced. These formulations require less active drug and the dosing accuracy requirements from a patient as well as legislative perspectives is as high as for other patient groups.
In contrast to dosing, where the dose normally is determined by metering a specific volume, pharmacopoeia requirements refer to mass, uniformity of mass and content uniformity (in % of mass).
When using volumetric dosing systems, mass of the dosed portion and uniformity of mass depend on precision of dose confinement and uniformity of product reservoir.
In the case of volumetric dosing of particles or pellets there are more to consider; changes e.g. in density, shape or particle size may lead to deviation in dosed weights, even if the metered volumes are the same.
Further, if the dose to be metered decreases compared to the size of the particles, or the pellets, the contribution from each individual particle or pellet increases. A normal dosing range constitutes 1000-10 000 particles or pellets. In formulations with less than 500 particles or pellets the experience is that those will generate an uncertainty of accuracy and precision in dosage content (precision of target weight) and content uniformity (high relative standard deviations).
In those cases, it is therefore appropriate to further control the dosing process, i.e. single weights and dose uniformity, by statistical IPC or by a 100% check-weighing. The weighing results are used to adjust the dosing system, thus minimizing rejects.
An example where indirect weighing is not accurate enough is when a small amount of pellets, in the range of 5 mg to 500 mg, have to be filled into sachets with tare weight of one to several grams.